As the world's population ages, neurodegenerative diseases have become increasingly important causes of morbidity and mortality. Aggregation of proteins such as alpha-synuclein in Parkinson's Disease (PD) and A beta and tau in Alzheimer's Disease represent a common pathophysiological feature. Despite this similarity, these diseases affect very different neuronal populations. Understanding selective vulnerability of neurons to toxic proteins is fundamental to developing treatments to diseases of aging. This proposal aims to understand selective neuronal vulnerability by testing the hypothesis that neurons affected by alpha-synuclein have a genetic expression profile that promotes alpha-synuclein toxicity. Preliminary studies using a C. elegans model of PD have shown that expressing alpha-synuclein in neurons causes an age- and concentration-dependent change in the animal's health and mobility. In Specific Aim 1, the temporal order in which neurons are affected by alpha-synuclein expression and their common characteristics will be demonstrated. Specific Aim 2 focuses on testing factors previously identified to affect selective vulnerability to alpha-synuclein and performing an unbiased screen to discover novel factors. In Specific Aim 3, the mechanisms by which these molecules promote selective neuronal are investigated. Few persons in society have not felt the impact of neurodegenerative diseases. Finding cures for these diseases would relieve a tremendous burden of human suffering and save this country's health care system millions of dollars. Understanding why certain neurons are affected early in PD would be a major step towards unraveling how these diseases develop and ultimately finding a cure. The candidate's career goal is to combine clinical care in Neurology with basic science and translational research in neurodegenerative diseases. She holds a Ph.D. in Physiology and an M.D. with Board Certification in Neurology and plans to pursue a career in academic medicine. As such, she has developed a research proposal and career development plan that build on her training in cell biology, molecular neurogenetics, basic neuroscience, and clinical neurology to study selective neuronal vulnerability in PD. This training will facilitate her goal of becoming an independent scientist. The work will be performed under the guidance of Drs. Cynthia Kenyon and Bruce Miller, both experts in aging and age-related diseases.